Influenza is a common respiratory infectious disease that spreads rapidly and is prone to mutation. According to statistics from the World Health Organization (WHO), there are approximately 1 billion cases of seasonal influenza worldwide each year. Vaccination is one of the most economical and effective means of preventing and controlling influenza. On January 15, 2025, Si Longlong's team from the Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, published two important research results in the two top international journals Nature Microbiology and Nature Chemical Biology at the same time, providing a new idea for the development of influenza vaccines.

Breakthrough 1: Constructing a PROTAR influenza vaccine library to expand vaccine diversity
Traditional vaccines have poor immune effects and safety risks when facing frequent virus mutations, and the development cycle is long and complicated. In 2022, Si Longlong's team pioneered the PROTAR attenuated live vaccine technology, using the "ubiquitin-proteasome system" to target and degrade viral proteins, and reduced the ability of the virus to replicate through a specific "life switch" element PTD, turning the virus into a safe and effective vaccine. In the study published in Nature Microbiology, the team established a PROTAR influenza vaccine library, further expanding the diversity of vaccines. By combining the characteristics of viral proteins with the diversity of E3 ubiquitin ligases, 22 types of PROTAR influenza vaccine strains were successfully constructed, providing rich options for vaccine research and development. In addition, the team innovatively designed engineered cells to improve the production efficiency and stability of vaccines, laying a solid foundation for the rapid preparation of influenza vaccines.

Breakthrough 2: Upgrading PROTAR Vaccine 2.0 to Improve Technical Flexibility and Versatility
Although the first-generation PROTAR vaccine technology is innovative, the PTD element can only be loaded at both ends of the viral protein, which has limitations in application. To address this problem, Si Longlong's team developed PROTAR vaccine 2.0 in a study published in Nature Chemical Biology. The new generation of technology allows PTD elements to be loaded at any position of the viral protein (including both ends and inside), and supports the simultaneous loading of multiple PTD elements, further improving the safety and immune effect of the vaccine. Experiments in canine kidney cells, mice and ferret models showed that PROTAR vaccine 2.0 has good safety, immunogenicity and a wide range of cross-immune protection effects, and can be extended to the development of various viral vaccines.

Expert evaluation: Provides a new direction for vaccine development
Gao Fu, an academician of the Chinese Academy of Sciences, said that this work has greatly enriched the diversity of influenza live attenuated vaccines and provided new ideas and methods for vaccine development. Zhao Guoping, an academician of the Chinese Academy of Sciences, commented: "This achievement has successfully promoted the development of new vaccine technology with the help of the principles of synthetic biology, demonstrating the great potential of synthetic biology in the prevention and control of infectious diseases."

Outlook: Synthetic biology drives a new era of vaccine development
This research result has not only made important breakthroughs in the field of influenza vaccines, but also provided a reference for the development of vaccines for other infectious diseases. As PROTAR technology continues to improve, it will be possible to quickly respond to emerging infectious diseases in the future and make important contributions to global public health prevention and control.

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